Several tetracycline class antibiotics have been known for over 50 years, but there have been relatively few commercially developed topical compositions that contain these antibiotics due to a number of challenges that must be addressed simultaneously in order to produce a commercially successful product.
Tetracycline class drugs, and minocycline in particular, are useful for the treatment of acne due to their anti-inflammatory effects. Their use for the treatment of acne has been demonstrated in orally delivered compositions that have shown good efficacy. However, the systemic delivery of tetracycline-class drugs is often accompanied by adverse side effects, such as diarrhea, abdominal cramps, and dizziness. High systemic levels of drug typically lead to greater systemic side effects. These can be beneficially reduced, for example, by using a topical composition that delivers a drug primarily to the skin, rather than primarily systemically. Unfortunately, topical formulations of tetracycline class drugs, such as minocycline, also have the potential for staining the skin, particularly after daily application over multiple weeks.
Intradermal or topical administration of a drug involves entry of the drug across the stratum corneum for a cutaneous or local skin effect; that is, the pharmacological effect of the drug is localized to the intracutaneous regions of drug penetration and deposition. Preferably, intradermal absorption occurs with little or no systemic absorption or accumulation. Intradermal absorption of a drug involves partitioning of the drug from the applied vehicle into the stratum corneum, diffusion of the drug through the stratum corneum, and partitioning of the drug from the stratum corneum into the epidermis. In contrast, transdermal administration involves transport of a drug through the skin such that a therapeutic amount of the drug is achieved in the systemic blood circulation.
Topical compositions that achieve delivery of a drug across the stratum corneum and retention of the majority of the drug intracutaneously such that it does not enter the bloodstream in significant amounts are challenging to design and require innovative approaches. Several factors determine the permeability of the skin or of particular layers of the skin to a topically-applied drug. These factors include the characteristics of the skin, the characteristics of the drug (e.g., its size (molecular weight or molecular volume), lipophilicity/hydrophilicity, polarity, etc.), the dosage of drug applied, the concentration and volume of the composition to be applied, interactions between the drug and the delivery vehicle, interactions between the drug and the skin, and interactions of the drug and the skin in the presence of the ingredients in the delivery vehicle. Because of the multitude of factors involved in the topical administration of a drug, it is generally accepted that whether intracutaneous delivery of a drug can be successfully achieved is uncertain. Thus, topical administration, while desired from a patient convenience and drug delivery view, has been largely unsuccessful for many compounds, including the tetracyclines, as evidenced by the relatively few drugs approved for topical administration.
One significant problem related to the topical administration of a tetracycline-class antibiotic is the identification of a solvent system in which the tetracycline class drug is stable, sufficiently soluble, and able to penetrate into a target tissue or body fluid, such as sebum.
Many tetracycline class drugs are sensitive to degradation by contact with and/or dissolution in hydrophilic oxidizing, reducing, or peroxidizing agents and/or water. As described in U.S. Patent Application Publication No. 2014/0147504, a major challenge in the development of topical formulations of minocycline has been its chemical nature—the drug is unstable in solution form and is also sensitive to moisture, temperature, and light. There have been several compositions that have been developed to address challenges associated with this drug. This instability applies to all currently available tetracycline class drugs.
Salman et al. describe, in U.S. Patent Application Publication No. 2014/0147504, a topical composition in which a tetracycline is suspended in a liquid medium that does not dissolve or minimally dissolves the tetracycline. While this approach is described as limiting the degradation of tetracycline, compositions in which the liquid medium does not dissolve the drug are not preferred due to the inability of the drug within the formulation to readily penetrate the skin. Since many products applied to the skin will be subject to rapid evaporation, it is likely that the drug will remain on the skin surface following its application. Such solid drug forms will not be bioavailable.
Another approach for maintaining the potency of a tetracycline drug is to separate it from potential reactive agents, such as with a coating or physical encapsulation of the drug, to limit its interaction/exposure to the potentially reactive agents. Physical encapsulation can be achieved by a wide variety of techniques. For example, Heggie et al. describe a composition for coating minocycline particles such that the particles are suspended in a solvent, rather than dissolved in it (U.S. Patent Application Publication No. 2013/0195986). However, this approach suffers from many of the same problems described above for use of a solvent system in which the drug is not dissolved.
Several proposed solvent systems, such as ointments, are not commercially viable for treatment of acne due to their possessing an oily feel. Even worse, some such substances may promote the condition that they are designed to treat, such as the use of a comedogenic material as a delivery vehicle for a composition designed to topically treat acne. Additionally, some strongly hydrophobic substances, such as petrolatum, paraffin wax, and/or fatty alcohol can produce an occlusive barrier that limits the drug penetration into the skin. Additionally, some hydrophobic substances have a high viscosity that limits the diffusion of the drug into the skin, thus reducing the bioavailability of the drug and limiting its effectiveness.
Compositions designed for use in non-topical areas have different constraints such that approaches or compositions developed for non-topical use may not be suitable for topical applications. For example, solutions for intravenous injection require an aqueous-based composition in order to be compatible with injection into the blood stream. However, since such injections are typically administered at hospitals and physician's offices with tighter controls on expiration dates and close ties to pharmacies, controlled storage conditions, such as refrigeration, may be more appropriate for intravenously delivered compositions in comparison to topical compositions which are typically stored by patients. In U.S. Patent Application Publication No. 2014/0194393, Griffith et al. propose stabilizing an aqueous minocycline composition using pH modifiers, magnesium chloride, and an antioxidant. However, a maximum stability of only 84.32% after 2 weeks under dark storage conditions at 37° C. is described for an exemplary minocycline composition. This level of stability is not sufficient for most drug applications. The stability of other compositions presented therein varies, but generally strongly aqueous environments do not promote stability for tetracycline class drugs.
Topically applied drug compositions are typically intended to deliver a drug uniformly to one or more depths within the skin tissue to which the composition is applied. However, bacteria for some dermatological conditions and diseases, such as P. acnes bacteria for acne, are located primarily in certain types of tissue, such as lipid-rich tissues including sebocytes, or body fluids, such as sebum. For such conditions and diseases, it is more efficient if the topical drug composition can be delivered preferentially to these locations where the bacteria are concentrated.
There is a need for a topically-applied composition that stabilizes an active tetracycline-class drug while enabling sufficient solubility in a delivery vehicle that delivers the drug to target tissue, such as sebaceous glands, or targets body fluids, such as sebum. The composition should maintain a high degree of potency, i.e., activity, of the drug, provide penetration into skin, sebum, and/or sebaceous glands in quantities sufficient to inhibit growth of Propionibacterium acnes (P. acnes) bacteria in these locations, and should not visibly stain the skin following repeated applications. Some compositions have been provided that meet one or more of these criteria, however, it would be desirable to provide a composition that meets all or most of these criteria in a single composition.